rs1060502290

Positions:

• chr9-95468878-G-A
• chr9-95468878-G-C
• chr9-95468878-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP6 BS2

The NM_000264.5(PTCH1):​c.2123C>T​(p.Thr708Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.44

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• BP6: Variant 9-95468878-G-A is Benign according to our data. Variant chr9-95468878-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409188.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2123C>T	p.Thr708Ile	missense_variant	14/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2120C>T	p.Thr707Ile	missense_variant	14/24	ENST00000437951.6	NP_001077072.1
LOC100507346	NR_038982.1	n.816G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2123C>T	p.Thr708Ile	missense_variant	14/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.2120C>T	p.Thr707Ile	missense_variant	14/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251408 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2022

The p.T708I variant (also known as c.2123C>T), located in coding exon 14 of the PTCH1 gene, results from a C to T substitution at nucleotide position 2123. The threonine at codon 708 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gorlin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;.;D;D;.;.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D
Polyphen		0.26	B;D;D;D;D;D;D
Vest4		0.82
MutPred		0.40		Gain of sheet (P = 0.0125);.;.;.;.;.;.;
MVP		0.56
MPC		1.4
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502290; hg19: chr9-98231160;